Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
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DOI：
10.1002/cpt.1375
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发表时间：
2019-07-01
影响因子：
6.7
通讯作者：
Daly, Ann K.
中科院分区：
文献类型：
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作者：
Nicoletti, Paola;Aithal, Guruprasad P.;Daly, Ann K.
一些接受氟氯西林（类似于0.01%）处方的患者发生药物性肝损伤（DILI）。HLA-B*57：01是氟氯西林DILI的既定遗传风险因素。为了巩固这一发现，确定其他遗传因素，并评估氟氯西林DILI的风险因素与其他青霉素引起的DILI的相关性，我们进行了一项涉及197例氟氯西林DILI病例和6，835例对照的全基因组关联研究。我们估算了单核苷酸多态性和人类白细胞抗原（HLA）基因型。HLA-B*57：01是主要的危险因素（等位基因优势比（OR）= 36.62; P = 2.67 × 10（-97））。HLA-B*57：03也显示出相关性（OR = 79.21; P = 1.2 x 10（-6））。在HLA-B蛋白序列中，插补显示HLA-B*57：01和HLA-B *57：03共有的缬氨酸（97）具有最大的影响（OR = 38.1; P = 9.7 x 10（-97））。我们没有发现HLA-B*57与其他异恶唑青霉素（n = 6）或阿莫西林（n = 15）引起的DILI相关，也没有发现任何青霉素相关DILI的显著非HLA信号。
Some patients prescribed flucloxacillin (similar to 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 x 10(-97)). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 x 10(-6)). Within the HLA-B protein sequence, imputation showed valine(97), common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 x 10(-97)). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.